MP

Molecular basis of human noradrenaline transporter reuptake and inhibition. 

Tan J, Xiao Y, Kong F, Zhang X, Xu H, Zhu A, Liu Y, Lei J, Tian B, Yuan Y, Yan C.

Nature. 2024 Aug;632(8026):921-929. 

doi: 10.1038/s41586-024-07719-z. Epub 2024 Jul 24. 

PMID: 39048818.

CryoEM structures of the human noradrenaline transporter (NET) in apo state and when bound to substrates or antidepressant drugs. 

=> noradrenaline and dopamine bind similarly within a central substrate site (S1) and a newly identified extracellular allosteric site (S2). 

4 antidepressants block substrate transport by occupying the S1 site in distinct conformations, with K+ observed in a Na+ binding site when NET is bound to desipramine.

An asymmetric nautilus-like HflK/C assembly controls FtsH proteolysis of membrane proteins. 

Ghanbarpour A, Telusma B, Powell BM, Zhang JJ, Bolstad I, Vargas C, Keller S, Baker T, Sauer RT, Davis JH.

bioRxiv [Preprint]. 2024 Aug 10:2024.08.09.604662. 

doi: 10.1101/2024.08.09.604662. 

PMID: 39149393. 

FtsH, a AAA protease, forms a MDa complex which spans the IM and reaches into the periplasm. 

Here: cryo-EM structures => HflK/C forms an asymmetric nautilus-like assembly = entryway for substrates to reach FtsH (enhancing its ability to degrade certain membrane-embedded proteins). 

The structure also shows membrane curvature associated with lipid-scramblase activity, which might be linked to the role of FtsH in protein degradation.

Proton-triggered rearrangement of the AMPA receptor N-terminal domains impacts receptor kinetics and synaptic localization. 

Ivica J, Kejzar N, Ho H, Stockwell I, Kuchtiak V, Scrutton AM, Nakagawa T, Greger IH.

Nat Struct Mol Biol. 2024 Aug 13. 

doi: 10.1038/s41594-024-01369-5. Epub ahead of print. 

PMID: 39138332.

AMPA glutamate receptors (AMPARs), crucial for fast excitatory synaptic transmission, are primarily influenced by the GluA2 subunit, which controls receptor localization and synaptic function through N-terminal domain (NTD). 

low pH => GluA2 NTD undergoes a conformational change due to protonation of a key histidine residue, disrupting its compact structure

=> slows receptor recovery from desensitization and increases receptor mobility.

Human mitochondrial carriers of the SLC25 family function as monomers exchanging substrates with a ping-pong kinetic mechanism. 

Cimadamore-Werthein C, King MS, Lacabanne D, Pyrihová E, Jaiquel Baron S, Kunji ER.

EMBO J. 2024 Aug;43(16):3450-3465. 

doi: 10.1038/s44318-024-00150-0. Epub 2024 Jun 27. 

PMID: 38937634.

The study challenges the long-held belief that certain SLC25 mitochondrial carriers function as dimers with a sequential kinetic mechanism. 

Most of these carriers are in fact monomers and operate with a ping-pong kinetic mechanism, where substrate import and export occur consecutively. 

Common transport mechanism involving a single substrate-binding site with alternates accessibility ?

Probing the formation of a hetero-dimeric membrane transport complex with dual in vitro and in silico mutagenesis. 

Rathod N, Lemieux MJ, Chipot C, Roux B, Young HS.

Chem Sci. 2024 Aug 6. 

doi: 10.1039/d4sc02915a. Epub ahead of print. 

PMID: 39156929.

The study investigates how the cardiac calcium regulator phospholamban (PLN) forms different oligomeric states and its role in inhibiting SERCA, a calcium pump. 

PLN = monomers and pentamers, with monomer inhibiting SERCA by forming a hetero-dimeric complex, while the pentamer = storage form. 

in silico calculations => binding affinities of PLN’s different forms estimated => the PLN pentamer likely interacts with SERCA, delivering a monomer to the inhibitory site. 

This suggests that the exchange of helices between oligomeric states is energetically favored over the involvement of a free monomer, highlighting a mechanism of conformational selection in membrane signaling.

Structure of the flotillin complex in a native membrane environment. 

Fu Z, MacKinnon R.

Proc Natl Acad Sci U S A. 2024 Jul 16;121(29):e2409334121. 

doi: 10.1073/pnas.2409334121. Epub 2024 Jul 10. 

PMID: 38985763.

CryoEM => Flotillin protein complex forms a right-handed helical barrel composed of 22 pairs of Flotillin1 and Flotillin2 subunits. 

The structure, stabilized by C-terminal helices and coiled-coil domains, interacts with membranes at both ends, potentially playing a role in membrane curvature. 

=> suggests a shared architecture among SPFH proteins and highlight Flotillin’s possible involvement in clathrin-independent endocytosis.

Cryo-EM structures of the human band 3 transporter indicate a transport mechanism involving the coupled movement of chloride and bicarbonate ions. 

Su CC, Zhang Z, Lyu M, Cui M, Yu EW.

PLoS Biol. 2024 Aug 21;22(8):e3002719. 

doi: 10.1371/journal.pbio.3002719. PMID: 39167625.

CryoEM of the human band 3 transporter, an essential protein in red blood cells that facilitates the exchange of bicarbonate and chloride ions across the membrane. 

=> 5 different structures showing that it can form both symmetric and asymmetric dimers with various outward-facing (OF) and inward-facing (IF) states (with a first model of the band 3 transporter in the IF conformation). 

Proposition of an elevator-type mechanism for ion transport.

Membranes

Structure-function relationships in pure archaeal bipolar tetraether lipids. 

Bhattacharya A, Falk ID, Moss FR 3rd, Weiss TM, Tran KN, Burns NZ, Boxer SG.

Chem Sci. 2024 Aug 7. 

doi: 10.1039/d4sc03788j. Epub ahead of print. 

PMID: 39149219.

Archaeal bipolar tetraether lipids (BTLs) = unique lipids believed to form a monolayer structure across membranes, providing extreme stability that helps archaea survive in harsh environments. 

Studying BTLs = challenging due to difficulties in obtaining pure samples. 

Here: chemical synthesis to create pure glycerol dialkyl glycerol tetraether (GDGT) lipids, allowing detailed biophysical investigations.

These lipids can form membrane-bound vesicles and reconstitute functional proteins. 

GDGT vesicles can undergo fusion ! => their membranes may transiently form bilayer structures, providing insights into how archaea perform essential physiological functions.

Optimizing Archaeal Lipid Biosynthesis in Escherichia coli. 

Hoekzema M, Jiang J, Driessen AJM.

ACS Synth Biol. 2024 Aug 16;13(8):2470-2479. 

doi: 10.1021/acssynbio.4c00235. Epub 2024 Aug 3. 

PMID: 39096298.

Archaea have distinct membrane lipid chemistry compared to bacteria and eukaryotes, a difference known as the lipid divide, which is reflected in their separate biosynthetic pathways. 

Here: increase of the production of archaeal lipids in E. coli by overexpressing an archaeal phosphatidylserine synthase and introducing a synthetic isoprenoid pathway. The engineered E. coli produced archaeal PL and novel hybrid species, showing increased sensitivity to cerulenin, which indicates a critical reliance on its native phospholipids.

Cryo-EM reconstruction of oleate hydratase bound to a phospholipid membrane bilayer. 

Oldham ML, Zuhaib Qayyum M, Kalathur RC, Rock CO, Radka CD.

J Struct Biol. 2024 Aug 14:108116. 

doi: 10.1016/j.jsb.2024.108116. Epub ahead of print. 

PMID: 39151742.

Oleate hydratase (OhyA) is a bacterial peripheral membrane protein involved in adding water to unsaturated FA + role in bacterial colonization by evading the immune system. 

Here: cryoEM to reveal the OhyA membrane complex, showing that OhyA maintains its structure and slightly modifies the liposome surface curvature upon binding. The protein prefers to associate with 20-30 nm liposomes, forming higher-order oligomers and demonstrating cooperative dimer assembly along liposome ridges.

The biogenesis and transport of triglyceride-rich lipoproteins. 

Zhang L, Wang X, Chen XW.

Trends Endocrinol Metab. 2024 Aug 19:S1043-2760(24)00196-6. 

doi: 10.1016/j.tem.2024.07.015. Epub ahead of print. 

PMID: 39164120.

Triglyceride-rich lipoproteins (TRLs) are crucial for lipid transport in the circulation. This review covers the mechanisms of TRL production, secretion, and regulation, emphasizing the complex interplay between biogenesis and transport processes (+ biology related to inherited diseases and viral infections).

A computational model for lipid-anchored polysaccharide export by the outer-membrane protein GfcD. 

Fruet C, Martinez-Goikoetxea M, Merino F, Lupas AN.

Biophys J. 2024 Aug 19:S0006-3495(24)00559-9. 

doi: 10.1016/j.bpj.2024.08.012. Epub ahead of print. 

PMID: 39164969.

Many bacteria are protected by polysaccharide capsules. The group 4 capsule in E coli involves the gfcABCDE-etp-etk operon. 

Here: GfcD, an OM β-barrel, studied for its role in exporting lipid-anchored polysaccharide chains, with AlphaFold predicting two β-barrel domains, including an unusual C-terminal barrel with a large lateral aperture. 

MD => lateral aperture of GfcD remains open, allowing lipid chains from the lipid A molecule to exit into the membrane, although membrane lipids do not penetrate the barrel.

A lumen-tunable triangular DNA nanopore for molecular sensing and cross-membrane transport. 

Liu X, Liu F, Chhabra H, Maffeo C, Chen Z, Huang Q, Aksimentiev A, Arai T.

Nat Commun. 2024 Aug 22;15(1):7210. 

doi: 10.1038/s41467-024-51630-0. 

PMID: 39174536.

Introduction of a triangular DNA nanopore with a tunable lumen that can expand or contract in response to specific DNA bindings, while maintaining its stable shape. 

TEM and MD: nanopore’s structure = high shape retention and stable architecture. 

single-channel current recordings and fluorescence influx: reliable, low-noise readouts and controlled macromolecular transport

=> potential applications in molecular sensing, drug delivery, and synthetic cells.

Native MS-guided lipidomics to define endogenous lipid microenvironments of eukaryotic receptors and transporters. 

Nat Protoc. 2024 Aug 22. 

doi: 10.1038/s41596-024-01037-4. Epub ahead of print. 

PMID: 39174660.

Method for identifying and quantifying endogenous lipids bound to mammalian MPs using native MS combined with lipidomics approaches. The approach allows direct assessment of copurified lipids and their affinities.

Molecules

Thiazine-derived compounds in inhibiting efflux pump in Staphylococcus aureus K2068, mepA gene expression, and membrane permeability alteration. 

Freitas PR, de Araújo ACJ, Araújo IM, de Almeida RS, Borges JAO, Paulo CLR, Oliveira-Tintino CDM, Miranda GM, Araújo-Neto JB, Nascimento IJS, Araújo-Júnior JX, Silva JMA, Balbino TCL, Silva-Júnior EF, Aquino TM, Mendonca-Junior FJB, Marinho ES, Santos HS, Lima CMG, Obaidullah AJ, Bin Emran T, Cunha FAB, Menezes IRA, Tintino SR, Coutinho HDM.

Biomed Pharmacother. 2024 Aug 14;179:117291. 

doi: 10.1016/j.biopha.2024.117291. Epub ahead of print. 

PMID: 39146766. 

Investigation of the inhibition of the MepA efflux pump in SA using thiadiazine-derived compounds. Two compounds directly affect the strain (one of them inhibits gene expression and alters membrane permeability).

A nondestructive membrane engineering method using an amphiphilic polymer. 

Kim NH, Shim G, Park GH, Yu YG.

Protein Sci. 2024 Sep;33(9):e5143. 

doi: 10.1002/pro.5143. 

PMID: 39150080.

Novel method for reconstituting MPs into live cells using amphiphilic poly-γ-glutamate (APG) => successfully applied to GPCRs, as well as the ligand-gated ion channel 5HT3A, without compromising cell viability. Reconstituted 5HT3A demonstrated ligand-dependent ion transport, and APG-mediated reconstitution in synthetic liposomes revealed that electrostatic interactions play a key role in the process.

Methods

Tunable Cytosolic Chloride Indicators for Real-Time Chloride Imaging in Live Cells. 

Morse J, Nadiveedhi MR, Schmidt M, Tang FK, Hladun C, Ganesh P, Qiu Z, Leung K.

bioRxiv [Preprint]. 2024 Aug 9:2024.08.08.606814. 

doi: 10.1101/2024.08.08.606814. 

PMID: 39149292.

Introduction of CytoCl dyes, a new series of cell-permeable, pH-independent fluorophores designed for real-time imaging of cytosolic chloride levels. These dyes enable the observation of rapid and transient chloride fluxes at the single-cell level, which was previously unachievable with steady-state imaging. The technique successfully captured proton-activated chloride channel activity, marking the first real-time visualization of ion flux through chloride channels in unmodified cells.

Evaluation of simplified ester-linked fatty acid analysis (ELFA) for phospholipid fatty acid (PLFA) analysis of bacterial population. 

Hwang JH, Choi TR, Kim S, Lee Y, Shin Y, Choi S, Oh J, Kim SH, Park JH, Bhatia SK, Yang YH.

Anal Biochem. 2024 Aug 8;695:115638. 

doi: 10.1016/j.ab.2024.115638. Epub ahead of print. 

PMID: 39127328.

Phospholipid fatty acid (PLFA) analysis (=characterization of microbial communities based on lipid profiles) is labor-intensive due to its requirement for lipid fractionation. 

Here: new method ”simplified ester-linked fatty acid analysis (ELFA)”, eliminates the need for fractionation by using base-catalyzed methylation to target only lipids, not free fatty acids. 

=> simpler procedure and improved detection of strain-specific markers.

Cell-free expression with a quartz crystal microbalance enables rapid, dynamic, and label-free characterization of membrane-interacting proteins. 

Khakimzhan A, Izri Z, Thompson S, Dmytrenko O, Fischer P, Beisel C, Noireaux V.

Commun Biol. 2024 Aug 17;7(1):1005. 

doi: 10.1038/s42003-024-06690-9. 

PMID: 39152195.

The TXTL-QCMD method = cell-free transcription-translation (TXTL) + quartz crystal microbalance with dissipation (QCMD) to dynamically study interactions between MPs and membranes without the need for purification or labeling.

Foam fractionation studies of recombinant human apolipoprotein A-I. 

Lethcoe K, Fox CA, Hafiane A, Kiss RS, Liu J, Ren G, Ryan RO.

Biochim Biophys Acta Biomembr. 2024 Aug 10;1866(7):184375. 

doi: 10.1016/j.bbamem.2024.184375. Epub ahead of print. 

PMID: 39128552.

Apolipoprotein A-I (apoA-I) = N-terminal α-helix bundle + hydrophobic C-terminal domain. When expressed in E. coli with the full-length construct, apoA-I was recovered in the cell lysate, whereas the truncated version lacking the C-terminal domain was secreted into the culture medium. 

Large-scale expression in a bioreactor => substantial foam production where truncated apoA-I (1-184) was the major protein ! 

This protein was successfully reconstituted into HDL particles with properties comparable to those made with full-length apoA-I, demonstrating a scalable method for producing a versatile HDL scaffold protein.

PLMC: Language Model of Protein Sequences Enhances Protein Crystallization Prediction. 

Xiong D, U K, Sun J, Cribbs AP.

Interdiscip Sci. 2024 Aug 19. 

doi: 10.1007/s12539-024-00639-6. Epub ahead of print. 

PMID: 39155325.

Description of PLMC, a new deep learning framework that utilizes a pre-trained protein language model and integrates both language embeddings and physicochemical features to improve the prediction of protein crystallization propensity.

PLMC significantly outperforms existing methods, achieving high AUC scores in predicting crystallization at various stages => potential to enhance experimental design for crystallizable protein variants.

SPOT-RASTR—a cryo-EM specimen preparation technique that overcomes problems with preferred orientation and the air/water interface. 

Esfahani, Behrouz Ghazi / Randolph, Peter S. / Peng, Ruizhi / Stroupe, Elizabeth / Grant, Tim / Stagg, Scott M.

cryo-EM faces challenges in specimen preparation, with issues such as aggregation and orientation at the air/water interface. 

Here: lipid nanotubes with Ni NTA headgroups as a new platform for cryo-EM, which protects samples from the interface and promotes better particle orientation. The method, combined with the RASTR technique to remove nanotubule signals, has been validated with β-galactosidase, showing improved particle detection, resolution, and the potential for fully automated data collection and structure determination.

Surface display provides an efficient expression system for production of recombinant proteins and bacterial whole cell biosensor in E. coli. 

Ramezani Khorsand F, Hakimi Naeini S, Molakarimi M, Dehnavi E, Zeinoddini M, Sajedi RH.

Anal Biochem. 2024 Nov;694:115599. 

doi: 10.1016/j.ab.2024.115599. Epub 2024 Jul 2. 

PMID: 38964699.

Novel bacterial display vector using E. coli developed for recombinant protein production and purification. 

Vector = fusion of EGFP with the ice nucleation protein (INP) for surface display, achieving a 57.7% recovery of EGFP as a single band on SDS-PAGE. 

The system was tested for copper ion detection with mutant EGFP, showing high sensitivity and a linear response in the low nM range for cell-displayed mutants and in the μM range for purified mutants = superior performance compared to purified proteins.

Agonist Discovery for Membrane Proteins on Live Cells by Using DNA-encoded Libraries. 

Huang Y, Hou R, Lam FS, Jia Y, Zhou Y, He X, Li G, Xiong F, Cao Y, Wang D, Li X.

J Am Chem Soc. 2024 Aug 22. 

doi: 10.1021/jacs.4c08624. Epub ahead of print. 

PMID: 39171830.

Novel approach for identifying biologically active ligands for membrane proteins using DNA-encoded libraries (DELs) directly on live cells to connect extracellular ligand binding with intracellular biochemical transformations, thus focusing on agonist identification.

Microbio

A coordinated attack by a bacterial secretion system and a small molecule drives prey specificity. 

Bier SB, Toska J, Zhao W, Suthianthong P, Proespraiwong P, Robins WP, Mekalanos J.

Commun Biol. 2024 Aug 8;7(1):958. 

doi: 10.1038/s42003-024-06637-0. 

PMID: 39117895.

Bacterial strains isolated from raw shrimp screened for those with bactericidal activity against Vibrio species.

Identification of Aeromonas dhakensis strain A603 => strong vibriocidal activity but limited effects on other Gram-negative bacteria. Genetic analysis of A603 revealed that its vibriocidal properties are due to a potent T6SS and the production of a phenazine-like molecule (Ad-Phen). 

Coregulation of Ad-Phen and the T6SS effector TseC => enhancement of the killing of Vibrio cholerae by Ad-Phen.

Miscellaneous

Spiders manipulate and exploit bioluminescent signals of fireflies. 

Fu X, Yu L, Zhou W, Lei C, Jackson RR, Kuntner M, Huang Q, Zhang S, Li D.

Curr Biol. 2024 Aug 19;34(16):R768-R769. 

doi: 10.1016/j.cub.2024.07.011. 

PMID: 39163834.

Orb-weaving spiders (Araneus ventricosus) make trapped male Absocondita terminalis fireflies flash like females to tempt more insects into their web. The spiders bite and wrap a flashing male firefly using a different technique than the one used on other prey. This method seems to change the repeating light sequence of the male firefly — which can still flash after being bitten — to one that resembles a female’s single pulse. The signal seems to tempt more males to their demise.

Pulling back the curtain

Jon Cohen & Abdullahi Tsanni

Science 16 Aug. 2024

doi: 10.1126/science.z3d5uwl 

Science must protect thinking time in a world of instant communication. 

Nature. 2024 Jul;631(8022):709. 

doi: 10.1038/d41586-024-02381-x. 

PMID: 39048687.

Nonlinear dynamics of multi-omics profiles during human aging. 

Shen X, Wang C, Zhou X, Zhou W, Hornburg D, Wu S, Snyder MP.

Nat Aging. 2024 Aug 14. 

doi: 10.1038/s43587-024-00692-2. Epub ahead of print. 

PMID: 39143318.

Ageing isn’t one long, slow decline — it happens in bursts at approximately 44 years and 60 years old. A deep dive into the health markers of more than 100 people in California found sudden shifts at those ages. In our 40s, there’s a change to the processes related to cardiovascular disease, and to metabolizing fatty compounds and alcohol. Then, in our 60s, comes a shift in immune regulation and carbohydrate metabolism.

Desiccated Cyanobacteria Serve As Efficient Plasmid DNA Carriers in Space Flight. 

Kakouridis A, Diamond S, Eng T, Mills HJ, Gámez Holzhaus O, Summers ML, Garcia-Pichel F, Mukhopadhyay A.

ACS Synth Biol. 2024 Aug 16. 

doi: 10.1021/acssynbio.3c00672. Epub ahead of print. 

PMID: 39150229.

Effective transport of biological systems is crucial for utilizing synthetic biology in space. 

Here: method using the desiccation-tolerant cyanobacterium Nostoc punctiforme to transport DNA plasmids to the International Space Station and back without the need for cryogenic storage. The plasmids remained intact and functional upon return, demonstrating that Nostoc punctiforme can serve as a robust transport system for genetic material in space missions.

Brain aging patterns in a large and diverse cohort of 49,482 individuals. 

Yang Z et al.

Nat Med. 2024 Aug 15. 

doi: 10.1038/s41591-024-03144-x. Epub ahead of print. 

PMID: 39147830.

An analysis of almost 50 000 brain scans has revealed five distinct patterns of brain atrophy associated with ageing and neurodegenerative disease. The analysis has also linked the patterns to lifestyle factors such as smoking and alcohol consumption as well as to genetic and blood-based markers associated with health status and disease risk. The work is a “methodological tour de force” says gerontologist Andrei Irimia. “We knew that brain anatomy changes with ageing and disease. But our ability to grasp this complex interaction was far more modest.”

A Personalized Brain Pacemaker for Parkinson’s

The New York Times

Published Aug. 19, 2024Updated Aug. 20, 2024

https://www.nytimes.com/2024/08/19/health/parkinsons-brain-pacemaker.html?smid=url-share

Neurologist Philip Starr and his colleagues designed a brain implant that applies deep-brain stimulation to treat the symptoms of Parkinson’s disease in a personalized way.